Respiratory syncytial virus (RSV) is a paramyxovirus that infects essentially all persons by their second birthday. Infants experiencing their first infection are most susceptible to lower airway infection in the form of bronchiolitis and pneumonia, but older adults and immunocompromised patients also experience severe RSV disease. In addition, this virus frequently reinfects healthy, immunocompetent individuals throughout life. Disease in seropositive adults and older children is usually limited to the upper airway, but significant virus shedding has been observed at each reinfection thus maintaining the virus within an immune population. The reason for this relatively ineffective immune response to RSV infection is not well understood, but the poor immunogenicity of this pathogen has so far confounded attempts to develop a safe and effective RSV vaccine. Currently there is no treatment for RSV, only transient prophylaxis in the form of a humanized monoclonal antibody targeting the RSV F protein. In a new approach to RSV vaccine design we made use of a viral vector derived from an avian paramyxovirus, Newcastle disease virus (NDV), chosen because it is known to be a very strong trigger for IFN-/ production in mammalian species As expected, intranasal instillation of recombinant NDV encoding the RSV F gene (NDV-F) into mice induced 1000 times more IFN-/ than did an equivalent dose of RSV, and 3 weeks after NDV-F priming mice were protected from live virus challenge. In addition, as we had hoped, NDV-F priming elicited significantly more RSV F protein-specific memory CD8+ T cells than did RSV itself. This result has now been reproduced in two additional rodent species (chinchillas and cotton rats).To test the NDV-F vaccine candidate for safety, efficacy, and establishment of long-lived protection we propose the following aims: 1) Generation of an optimized NDV-F vaccine candidate. 2) Assessment of T and B cell responses to the HRSV F protein following NDV-F priming, protection from live virus challenge, histopathology, and immunological memory in the cotton rat. 3) Assessment of T and B cell responses to the BRSV F protein following NDV-FB priming, protection from live virus challenge, histopathology, and immunological memory in the cow. 4) Large scale production of genetically stable NDV-F under GMP conditions. There is a large body of evidence to suggest that vaccinations placed in the nose may be the most effective means of protection against respiratory viruses. Our laboratory is working to develop an intranasal vaccine against respiratory syncytial virus, a virus responsible for the majority of nose and lung infections in children. The approach involves using Newcastle disease virus (NDV), which is not harmful to humans, to deliver pieces of RSV for processing by the immune system. This idea has worked very well in mice; one dose of the vaccine protects the animals from being infected later with RSV. In this proposal we will test this vaccine for safety and effectiveness in cotton rats and cattle, the animals who suffer a similar disease with this virus. If it appears safe and effective, we can move this into human trials.